Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Pseudomonas aeruginosa lung infection is the leading cause of death in individuals with the genetic disease cystic fibrosis(CF). CF leads to excessive mucus secretion from airway epithelial cells (AECs) and inflammation in the lungs. Early in life, CF patients suffer with transient acute P. aeruginosa infections that can be cured by antibiotic treatment coupled with the patient's own innate immune system. By late adolescence, however, the lungs of most (~80%) CF patients are chronically infected with P. aeruginosa and this cannot be eradicated by any known therapy. Chronic infections aggravate inflammation in the CF lung, leading to progressive and irreversible damage of tissues. The phenotypic properties of P. aeruginosa associated with acute infections are very different from those that chronically colonize CF airways. This study aims to determine whether the different phenotypic properties adopted by P. aeruginosa during acute and chronic infections elicit different inflammatory responses from CF AECs. I will characterize the inflammatory response of CF AECs to P.aeruginosa clinical isolates that are collected "early" from patients (during acute infections) versus those isolates that are collected "late" (during chronic infections). I expect that P. aeruginosa "early" and "late" isolates will elicit different patterns of inflammation from CF AECs. I also expect that the pattern of inflammation elicited by "late" isolates will preclude bacterial clearance by the innate immune system and facilitate bacterial persistence in CF airways. Determining how Pa alters the inflammatory response of AECs during chronic infection is crucial for understanding how Pa causes respiratory failure in the CF lung. By understanding the mechanism(s) by which Pa stimulates an aberrant inflammatory response in CF AECs, this research is poised to reveal new biological targets for the rational design of drugs against chronic Pa infections in the CF lung.